The ultimate goal of this research is to achieve the induction of clinical tolerance (antigen specific unresponsiveness) allowing the long- term survival of human organ allografts. Collaborative studies between the Krensky, Clayberger, and Parham laboratories have shown that synthetic peptides corresponding to linear sequences of HLA class I molecules are potent inhibitors of the allogeneic immune response, both in vitro and in vivo. The objectives of the studies proposed here are to broaden our understanding of this phenomenon by elucidating the mechanisms responsible for these effects (Project 1), to define the ligand(s) and binding characteristics involved (Project 2), to extend pre-clinical studies in rat transplantation models (Project 3), and, eventually to develop a protocol applicable to human allogeneic organ transplantation. These projects are supported by an Administrative Core (A) designed to ensure unity of purpose and quality control and a Peptide Chemistry Core (B) responsible for peptide synthesis and modification. This program builds upon established collaborations between transplant clinicians, clinical scientists, and basic immunologists in order to rapidly apply knowledge obtained from basic research to clinical practice. This proposal is designed to provide a rational basis for the application of HLA derived peptides to transplantation. It is aimed at providing the foundation for renewal application which would propose specific human trials and uniquely monitor the human in vivo immune response to such therapies.